PROJECT SUMMARY/ABSTRACT Schistosomiasis continues to be among the most prevalent of Neglected Tropical Diseases, a global health threat, taking the largest toll on those who have the fewest resources?the so-called ?bottom billion?. This disease has proven to be difficult to control. Indeed, recent global estimates are 20% higher than estimates of 50 years ago (currently 258 million cases). Schistosomiasis remains stubbornly entrenched in many endemic areas, especially Sub-Saharan Africa where 85% of cases now occur. The World Health Organization (WHO) has called for the elimination of human schistosomiasis as a public health problem by 2025, with mass drug administration of a single available drug, praziquantel, as the main tool to combat this parasite. However, a more integrated approach including sanitation, hygiene, vaccine development and snail vector control will be necessary to reach these ambitious goals. Methods aimed at using natural genetic resistance of snails to schistosomes are being explored; however, almost all of these studies have used laboratory models of South American snails (Biomphalaria glabrata) and schistosomes (Schistosoma mansoni), but the majority of S. mansoni transmission occurs through African species of Biomphalaria. It is unclear how well knowledge gained from laboratory models will translate across species to African snails in natural transmission zones. Thus, in order to develop genetically based snail control in highly endemic areas, there is a critical need to determine genetic mechanisms of vector competence in those wild populations of snails. We propose to address this need through a combined field and laboratory-model based approach. Firstly, we will use a genome wide association study (GWAS) on wild snails (B. sudanica) collected from hotspot transmission sites in Lake Victoria, Kenya, to find schistosome resistance genes. GWAS uncovers genes with the largest effect first?those that are the most ideal for schistosomiasis control. Secondly, we will test whether 8 genes known to influence resistance in B. glabrata also influence resistance in B. sudanica. This will be done using outbred snails from the natural population, and inbred lines derived from the same population. Characterizing the inbred lines will also establish a laboratory model for B. sudanica, which will be essential for functional testing of candidate genes. Thirdly, we will sequence and assemble the genome of B. sudanica, which will not only facilitate our GWAS and candidate gene testing, but will serve as an important resource for future vector-control studies. Finally, our project will also address an important training need as expertise in medical malacology is declining. These skills will be necessary for schistosome elimination programs of the future. Our proposed studies will be the first step in developing control measures aimed at reducing snail-schistosome compatibility using naturally occurring genetic variation in African snails in an important transmission zone.